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J Pediatr Infect Dis 2023; 18(04): 186-192
DOI: 10.1055/s-0043-57249
Original Article

Effect of Antibiotics and Gut Microbiota on the Development of Sepsis in Children with Hematopoietic Stem Cell Transplants

Daniela Potes   *
1   TAO-Lab/CiBioFi Laboratory, Department of Biology, Faculty of Natural and Exact Sciences, Universidad del Valle, Cali, Colombia
,
Iván Darío Benavides   *
2   Department of Pediatrics, Universidad del Valle, Cali, Colombia
3   Bone Marrow Transplant Unit, Clínica Imbanaco Grupo Quironsalud, Cali, Colombia
,
Nelson Rivera-Franco
1   TAO-Lab/CiBioFi Laboratory, Department of Biology, Faculty of Natural and Exact Sciences, Universidad del Valle, Cali, Colombia
,
Carlos A. Portilla
2   Department of Pediatrics, Universidad del Valle, Cali, Colombia
3   Bone Marrow Transplant Unit, Clínica Imbanaco Grupo Quironsalud, Cali, Colombia
4   Fundación POHEMA, Cali, Colombia
,
Oscar Ramirez
3   Bone Marrow Transplant Unit, Clínica Imbanaco Grupo Quironsalud, Cali, Colombia
4   Fundación POHEMA, Cali, Colombia
,
Andrés Castillo
1   TAO-Lab/CiBioFi Laboratory, Department of Biology, Faculty of Natural and Exact Sciences, Universidad del Valle, Cali, Colombia
5   Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
,
Eduardo López-Medina 
2   Department of Pediatrics, Universidad del Valle, Cali, Colombia
3   Bone Marrow Transplant Unit, Clínica Imbanaco Grupo Quironsalud, Cali, Colombia
6   Centro de Estudios en Infectología Pediátrica, Cali, Colombia
› Author Affiliations Funding Funding was received from Universidad del Valle, project code: CI 1870.
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Abstract

Objective To describe the association between antibiotic use, gut microbiota composition, and the development of sepsis in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) to treat acute lymphoblastic leukemia.

Methods A cohort of pediatric patients was followed up between days −30 (pre-HSCT) and +30 (post-HSCT), and sequential stool samples were collected for analysis of the taxonomic composition of bacterial communities by comparing the sequences of the 16s ribosomal RNA gene. Clinically, patients were divided into those with or without sepsis according to their clinical and laboratory data. Gut microbiota was categorized as potentially pathogenic or commensal and was described according to antibiotic use in patients with and without sepsis.

Results A cohort of eight patients provided 34 stool samples at different time points during their pre- and post-HSCT periods. There was a greater diversity in the microbial composition in patients who did not develop sepsis. In contrast, patients who developed sepsis had low microbiota diversity, a slight dominance of the genus Bacteroides and order Enterobacterales, and a low abundance of the genus Akkermansia. The use of antibiotics was associated with a low relative abundance of commensal bacteria, a high relative abundance of potentially pathogenic microbiota, and a risk of sepsis.

Conclusion Our results suggest that gut microbiota sequencing in pediatric HSCT recipients could predict the clinical course and guide direct interventions to improve patient outcomes. Accordingly, short-spectrum, tailored antibiotic therapy could be provided to patients with fever pre- and post-HSCT to prevent dysbiosis and reduce the risk of sepsis.

Keywords

gastrointestinal microbiota - sepsis - acute lymphoblastic leukemia - children - hematopoietic stem cell transplantation - dysbiosis

Note

These data were shown, in part, as a poster presentation at the 2020 Transplantation and Cellular Therapy Meetings, Orlando, Florida, United States; February 19–23, 2020.


* These authors contributed equally.




Publication History

Received: 04 January 2023

Accepted: 27 March 2023

Article published online:
19 April 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Ramirez Wurttemberger O. Information and childhood cancer. Colomb Med (Cali) 2016; 47 (02) 74-75
    CrossrefPubMedGoogle Scholar
  • 2 Hertl M. Trasplante de precursones hematopoyéticos, 2020. Accessed February 12, 2022, at: https://www.msdmanuals.com/es-co/professional/inmunología-y-trastornos-alérgicos/trasplante/trasplante-de-células-madre-hematopoyéticas
    PubMed
  • 3 Mori Y, Yoshimoto G, Nishida R. et al. Gastrointestinal graft-versus-host disease is a risk factor for postengraftment bloodstream infection in allogeneic hematopoietic stem cell transplant recipients. Biol Blood Marrow Transplant 2018; 24 (11) 2302-2309
    CrossrefPubMedGoogle Scholar
  • 4 Pastores SM, Papadopoulos E, van den Brink M, Alicea M, Halpern NA. Septic shock and multiple organ failure after hematopoietic stem cell transplantation: treatment with recombinant human activated protein C. Bone Marrow Transplant 2002; 30 (02) 131-134
    CrossrefPubMedGoogle Scholar
  • 5 Frosali S, Pagliari D, Gambassi G, Landolfi R, Pandolfi F, Cianci R. How the intricate interaction among toll-like receptors, microbiota, and intestinal immunity can influence gastrointestinal pathology. J Immunol Res 2015; 2015: 489821
    CrossrefPubMedGoogle Scholar
  • 6 Taur Y, Jenq RR, Perales MA. et al. The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood 2014; 124 (07) 1174-1182
    CrossrefPubMedGoogle Scholar
  • 7 McGuckin MA, Lindén SK, Sutton P, Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol 2011; 9 (04) 265-278
    CrossrefPubMedGoogle Scholar
  • 8 Cheng H, Guan X, Chen D, Ma W. The Th17/Treg cell balance: a gut microbiota-modulated story. Microorganisms 2019; 7 (12) 583
    CrossrefPubMedGoogle Scholar
  • 9 Du B, Shen N, Tao Y. et al. Analysis of gut microbiota alteration and application as an auxiliary prognostic marker for sepsis in children: a pilot study. Transl Pediatr 2021; 10 (06) 1647-1657
    CrossrefPubMedGoogle Scholar
  • 10 Lin D, Hu B, Li P, Zhao Y, Xu Y, Wu D. Roles of the intestinal microbiota and microbial metabolites in acute GVHD. Exp Hematol Oncol 2021; 10 (01) 49
    CrossrefPubMedGoogle Scholar
  • 11 Taur Y, Xavier JB, Lipuma L. et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation. Clin Infect Dis 2012; 55 (07) 905-914
    CrossrefPubMedGoogle Scholar
  • 12 Jenq RR, Taur Y, Devlin SM. et al. Intestinal Blautia is associated with reduced death from graft-versus-host disease. Biol Blood Marrow Transplant 2015; 21 (08) 1373-1383
    CrossrefPubMedGoogle Scholar
  • 13 Sahitya DSK, Jandiyal A, Jain A. et al. Prevention and management of carbapenem-resistant Enterobacteriaceae in haematopoietic cell transplantation. Ther Adv Infect Dis 2021; 8: 20 499361211053480
    PubMedGoogle Scholar
  • 14 Herlemann DP, Labrenz M, Jürgens K, Bertilsson S, Waniek JJ, Andersson AF. Transitions in bacterial communities along the 2000 km salinity gradient of the Baltic Sea. ISME J 2011; 5 (10) 1571-1579
    CrossrefPubMedGoogle Scholar
  • 15 Volant S, Lechat P, Woringer P. et al. SHAMAN: a user-friendly website for metataxonomic analysis from raw reads to statistical analysis. BMC Bioinformatics 2020; 21 (01) 345
    CrossrefPubMedGoogle Scholar
  • 16 Quast C, Pruesse E, Yilmaz P. et al. The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 2013; 41 (Database issue): D590-D596
    CrossrefPubMedGoogle Scholar
  • 17 McMurdie PJ, Holmes S. phyloseq: an R package for reproducible interactive analysis and graphics of microbiome census data. PLoS One 2013; 8 (04) e61217
    CrossrefPubMedGoogle Scholar
  • 18 Wickham H. Ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2016
    CrossrefGoogle Scholar
  • 19 Shannon CE. A mathematical theory of communication. The Bell System Technical Journal 1948; 27 (03) 379-423
    CrossrefPubMedGoogle Scholar
  • 20 Odum EP, Barrett GW, Ortega MTA. Fundamentos de Ecología. Quinta Edición. México: Thomson; 2006
    Google Scholar
  • 21 Quinto-Mosquera H, Hurtado D, Arboleda J. Influencia de las condiciones edáficas sobre la dominancia y diversidad de árboles en bosques pluviales tropicales del Chocó biogeográfico. Rev Biol Trop 2019; 67 (06) 1278-1291
    PubMedGoogle Scholar
  • 22 Plunkett A, Tong J. Sepsis in children. BMJ 2015; 350: h3017
    CrossrefPubMedGoogle Scholar
  • 23 Toro JF, Peña E, Ramírez O, López P, Portilla CA, López-Medina E. Routine use of biomarkers to rationalize antibiotic use during febrile episodes in pediatric bone marrow transplantation units. Pediatr Infect Dis J 2021; 40 (11) 1023-1028
    CrossrefPubMedGoogle Scholar
  • 24 GBD 2019 Antimicrobial Resistance Collaborators. Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet 2022; 400 (10369): 2221-2248
    CrossrefPubMedGoogle Scholar
  • 25 Droz N, Hsia Y, Ellis S, Dramowski A, Sharland M, Basmaci R. Bacterial pathogens and resistance causing community acquired paediatric bloodstream infections in low- and middle-income countries: a systematic review and meta-analysis. Antimicrob Resist Infect Control 2019; 8: 207
    CrossrefPubMedGoogle Scholar
  • 26 Andermann TM, Peled JU, Ho C. et al; Blood and Marrow Transplant Clinical Trials Network. The microbiome and hematopoietic cell transplantation: past, present, and future. Biol Blood Marrow Transplant 2018; 24 (07) 1322-1340
    CrossrefPubMedGoogle Scholar
  • 27 Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell 2018; 33 (04) 570-580
    CrossrefPubMedGoogle Scholar
  • 28 Koh AY. The microbiome in hematopoietic stem cell transplant recipients and cancer patients: opportunities for clinical advances that reduce infection. PLoS Pathog 2017; 13 (06) e1006342
    CrossrefPubMedGoogle Scholar
  • 29 Patrick S. Bacteroides . In: Tang YW, Sussman M, Liu D, Poxton I, Schwartzman J, eds. Molecular Medical Microbiology. 2nd ed. London: Academic Press; 2015: 917-944
    Google Scholar
  • 30 Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis 2008; 8 (03) 159-166
    CrossrefPubMedGoogle Scholar
  • 31 Kusakabe S, Fukushima K, Maeda T. et al. Pre- and post-serial metagenomic analysis of gut microbiota as a prognostic factor in patients undergoing haematopoietic stem cell transplantation. Br J Haematol 2020; 188 (03) 438-449
    CrossrefPubMedGoogle Scholar
  • 32 Gophna U, Konikoff T, Nielsen HB. Oscillospira and related bacteria - from metagenomic species to metabolic features. Environ Microbiol 2017; 19 (03) 835-841
    CrossrefPubMedGoogle Scholar
  • 33 Wing JB, Tanaka A, Sakaguchi S. Human FOXP3+ regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 2019; 50 (02) 302-316
    CrossrefPubMedGoogle Scholar
  • 34 Kaysen A, Heintz-Buschart A, Muller EEL. et al. Integrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation. Transl Res 2017; 186: 79-94 .e1
    CrossrefPubMedGoogle Scholar
  • 35 Druart C, Plovier H, Van Hul M. et al. Toxicological safety evaluation of pasteurized Akkermansia muciniphila . J Appl Toxicol 2021; 41 (02) 276-290
    CrossrefPubMedGoogle Scholar
  • 36 Zhang T, Li Q, Cheng L, Buch H, Zhang F. Akkermansia muciniphila is a promising probiotic. Microb Biotechnol 2019; 12 (06) 1109-1125
    CrossrefPubMedGoogle Scholar
  • 37 EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA). Turck D, Bohn T, Castenmiller J. et al. Safety of pasteurised Akkermansia muciniphila as a novel food pursuant to Regulation (EU) 2015/2283. EFSA J 2021; 19 (09) e06780
    CrossrefPubMedGoogle Scholar
  • 38 Luo Y, Lan C, Li H. et al. Rational consideration of Akkermansia muciniphila targeting intestinal health: advantages and challenges. NPJ Biofilms Microbiomes 2022; 8 (01) 81
    CrossrefPubMedGoogle Scholar
  • 39 Bilinski J, Robak K, Peric Z. et al. Impact of gut colonization by antibiotic-resistant bacteria on the outcomes of allogeneic hematopoietic stem cell transplantation: a retrospective, single-center study. Biol Blood Marrow Transplant 2016; 22 (06) 1087-1093
    CrossrefPubMedGoogle Scholar
  • 40 Nishi K, Kanda J, Hishizawa M. et al. Impact of the use and type of antibiotics on acute graft-versus-host disease. Biol Blood Marrow Transplant 2018; 24 (11) 2178-2183
    CrossrefPubMedGoogle Scholar